Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
Medulloblastoma is the most common malignant brain tumor in children. Despite the progress in the current tumor treatment, including surgery, chemotherapy and radiotherapy, more than 30% of medulloblastoma patients still die within 5 years after the diagnosis. Moreover, the survivors often suffer severe side effects of tumor treatment, including endocrine disorders, coordination problems and increased tumor incidence in other parts of the body. Therefore, improved strategies to treating medulloblastoma are highly needed.
Sonic hedgehog (Shh) signaling pathway plays a role in normal mammalian development, especially the proliferation of neuronal progenitors cells. Aberrant activation of this signaling is associated to the development of many malignancies including medulloblastoma, Basal cell carcinoma and rhabdomyosarcoma (Rubin, L L et al. (2006). Nat. Rev. Drug Discov. 5:1026-33). In studying the etiology of medulloblatoma, a conditional knockout mouse model (Math1-Cre/Ptch1C/C mice) was previously generated in which Patched1, an antagonist of Shh signaling, is deleted specifically in cerebellar granule neuron precursors (Yang Z J et al. (2008) Cancer Cell 14, 135-45). These animals develop tumors in their cerebellum, which resemble human medulloblastoma in their marker expression, cell morphology and genetic profiles. These studies have demonstrated that cerebellar GNPs represent cellular origin for medullobalstoma, and highlighted the importance of Shh signaling in the tumorigenesis of medulloblastoma.
Due to the role of Shh signaling in carcinogenesis, many Shh signaling inhibitors have been developed as potential anticancer agents (Sahebjam, S et al. (2012) Oncologist 17:1090-99.). The early data generated from these inhibitors held promise for some tumor types, especially in patients with Basal Cell Carcinoma. However, since the Shh pathway is required for normal development, severe on-target adverse effects of inhibiting the Shh pathway have been observed (Ohba, S. et al. (2008) Dev. Cell 14:689-99), which limits the suitability of such potential treatments. Indeed, it has been reported that transient inhibition of the Shh pathway in mice has resulted in permanent bone defects and altered growth, which persisted after cessation of the Shh pathway inhibitor and restoration of pathway (Kimura, H et al. (2008) Cancer Cell 13:249-60). This has greatly hampered the clinical application of general Shh pathway inhibitors in cancer treatment. Shh pathway inhibitors that selectively target tumor cells over healthy cells are needed.